CXCL9, CXCL10, and CXCL11; biomarkers of pulmonary inflammation associated with autoimmunity in patients with collagen vascular diseases–associated interstitial lung disease and interstitial pneumonia with autoimmune features

Masami Kameda; Mitsuo Otsuka; Hirofumi Chiba; Koji Kuronuma; Takehiro Hasegawa; Hiroki Takahashi; Hiroki Takahashi

doi:10.1371/journal.pone.0241719

Peer Review History

Original SubmissionJuly 23, 2020
8 Sep 2020 Decision Letter - Masataka Kuwana, Editor PONE-D-20-22949 CXCL9, CXCL10, and CXCL11; Biomarkers of pulmonary inflammation associated with autoimmunity in patients with collagen vascular diseases–associated interstitial lung disease and interstitial pneumonia with autoimmune features. PLOS ONE Dear Dr. Kuronuma, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Our reviewers found some interests in this study, but also pointed out a number of criticisms that are useful for improving this manuscript. I ask the authors to fully respond to all comments made by reviewers in the revised version. Please submit your revised manuscript by Oct 23 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols We look forward to receiving your revised manuscript. Kind regards, Masataka Kuwana, MD, PhD Academic Editor PLOS ONE Journal Requirements: When submitting your revision, we need you to address these additional requirements. 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. 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Please add a citation to support this phrase or upload the data that corresponds with these findings to a stable repository (such as Figshare or Dryad) and provide and URLs, DOIs, or accession numbers that may be used to access these data. Or, if the data are not a core part of the research being presented in your study, we ask that you remove the phrase that refers to these data. 4.Thank you for providing the following Funding Statement: [MK, MO, and HT received funding from Sysmex Corp. TH is an employee of Sysmex Corp. T.H. contributed to the measurement of cytokines. The funder had no control over the interpretation, writing, or publication of this work.]. We note that one or more of the authors is affiliated with the funding organization, indicating the funder may have had some role in the design, data collection, analysis or preparation of your manuscript for publication; in other words, the funder played an indirect role through the participation of the co-authors. 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This information should be included in your cover letter; we will change the online submission form on your behalf. Please know it is PLOS ONE policy for corresponding authors to declare, on behalf of all authors, all potential competing interests for the purposes of transparency. PLOS defines a competing interest as anything that interferes with, or could reasonably be perceived as interfering with, the full and objective presentation, peer review, editorial decision-making, or publication of research or non-research articles submitted to one of the journals. Competing interests can be financial or non-financial, professional, or personal. Competing interests can arise in relationship to an organization or another person. Please follow this link to our website for more details on competing interests: http://journals.plos.org/plosone/s/competing-interests [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Partly ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: The authors evaluated the cytokine levels in serum and BALF, and found that serum CXCL9, CXCL10, and CXCL11 are useful biomarkers for autoimmune inflammation and predictors of immunosuppressant responses in ILD. Although the effect of the anti-fibrotic drug, nintedanib, on progressive fibrosing ILD has been already established, anti-inflammatory drugs are also effective in some ILD, including CVD-ILD and IPAF. However, there is currently no established biomarkers and treatments for them (anti-inflammatory drug or anti-fibrotic drug, or both?). This study provides an important contribution to the biomarker for patients who use anti-inflammatory drugs. <major comments=""> The authors described that CXCL9, CXCL10, and CXCL11 are important for the diagnosis of CVD-ILD and IPAF and anti-inflammatory therapy. However, it is unclear how to use these biomarkers in clinical practice. It would be informative to discuss the clinical application of these biomarkers. <minor comments=""> L141 cytokiness→cytokines P11L182 Indicate the actual measurement value in the results (same below)</minor></major> Reviewer #2: <general comments=""> In this manuscript, Kameda and colleagues assessed serum and BALF levels of various cytokines, including CXCL9, CXCL10, and CXCL11, in patients with CVD-ILD, IPAF and IPF. They also assessed clinical significance of these cytokine levels (CXCL9, CXCL10, and CXCL11) in serum and BALF, regarding association of clinical variables, diagnoses and response to immunosuppressive therapy. They found that serum and BALF levels of CXCL9, CXCL10, and CXCL11 were elevated in patients with CVD-ILD or IPAF compared with IPF. Levels of these chemokine were correlated with several clinical variables. In 10 patients with CVD-ILD or IPAF who treated with corticosteroid and/or immunosuppressive agents, serum CXCL9 and CXCL11 levels were positively associated with annual FVC changes. According to these findings, they concluded that CXCL9, CXCL10 and CXCL11 may be biomarkers to evaluate autoimmune inflammation and to predict response to immunosuppressive treatments. Their findings highlight interesting aspects of distinct pathophysiology among CVD-ILD, IPAF and IFP, however, there are several concerns in this study. As described in the limitation by the authors, the number of the patients, especially patients with CVD-ILD, were very small. Additionally, CVD-ILD contain variety of diseases, such as RA, Ssc, PM, MCTD and SS, which have different pathophysiology, respectively. Moreover, the number of patients who treated by immunosuppressive agent were only 10, which was too small to indicate that serum CXCL9 and CXCL11 are potential biomarker to predict response to immunosuppressive therapy. <comments> The authors showed the association between CXCL9, CXCL10 and CXCL11 levels and clinical variables, such as %FVC, %DLCO, A-aDO2, CRP and BALF findings in all the patient in Table 4 (page 15, 16). As the levels of these markers differed among CVD-ILD, IPAF and IPF, the correlations between these markers and clinical variables may be different among the three groups. The author should explain these points or assess the correlations in each group, respectively. The authors showed the association between serum CXCL9, CXCL10 or CXCL11 levels and FVC change in 10 patients who treated with corticosteroid and/or immunosuppressive agents in CVD-ILD and IPAF groups in Figure 2 (page 17). This study include 16 patients with CDV-ILD and 35 patients with IPAF. In that case, how the 41 patients in CVD-ILD and IPAF groups were treated? The majority of the patients (41 patients) in CVD-ILD and IPAF groups did not receive corticosteroid and/or immunosuppressive agents? It is unclear how the authors chose the 10 patients for the correlation analyses between serum markers and response to treatment?</comments></general> ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review?** For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0241719.r001
Revision 1
28 Sep 2020 Author Response Reviewer #1: The authors evaluated the cytokine levels in serum and BALF, and found that serum CXCL9, CXCL10, and CXCL11 are useful biomarkers for autoimmune inflammation and predictors of immunosuppressant responses in ILD. Although the effect of the anti-fibrotic drug, nintedanib, on progressive fibrosing ILD has been already established, anti-inflammatory drugs are also effective in some ILD, including CVD-ILD and IPAF. However, there is currently no established biomarkers and treatments for them (anti-inflammatory drug or anti-fibrotic drug, or both?). This study provides an important contribution to the biomarker for patients who use anti-inflammatory drugs. -> We thank the reviewer 1 for the positive overall evaluation of our study. The authors described that CXCL9, CXCL10, and CXCL11 are important for the diagnosis of CVD-ILD and IPAF and anti-inflammatory therapy. However, it is unclear how to use these biomarkers in clinical practice. It would be informative to discuss the clinical application of these biomarkers. -> We appreciate the precise comments. We added the sentence below at lane 361-363. These serum biomarkers may enable clinicians to more easily evaluate when and to whom to administer anti-inflammatory drugs with simple blood tests in ILD management. L141 cytokiness→cytokines -> We corrected. P11L182 Indicate the actual measurement value in the results (same below) -> We added the measured value in the results. Please confirm the lanes 178-190, 210-213, 228-231, 246-247, 253-267, and 296. Reviewer #2: In this manuscript, Kameda and colleagues assessed serum and BALF levels of various cytokines, including CXCL9, CXCL10, and CXCL11, in patients with CVD-ILD, IPAF and IPF. They also assessed clinical significance of these cytokine levels (CXCL9, CXCL10, and CXCL11) in serum and BALF, regarding association of clinical variables, diagnoses and response to immunosuppressive therapy. They found that serum and BALF levels of CXCL9, CXCL10, and CXCL11 were elevated in patients with CVD-ILD or IPAF compared with IPF. Levels of these chemokine were correlated with several clinical variables. In 10 patients with CVD-ILD or IPAF who treated with corticosteroid and/or immunosuppressive agents, serum CXCL9 and CXCL11 levels were positively associated with annual FVC changes. According to these findings, they concluded that CXCL9, CXCL10 and CXCL11 may be biomarkers to evaluate autoimmune inflammation and to predict response to immunosuppressive treatments. Their findings highlight interesting aspects of distinct pathophysiology among CVD-ILD, IPAF and IFP, however, there are several concerns in this study. As described in the limitation by the authors, the number of the patients, especially patients with CVD-ILD, were very small. Additionally, CVD-ILD contain variety of diseases, such as RA, Ssc, PM, MCTD and SS, which have different pathophysiology, respectively. Moreover, the number of patients who treated by immunosuppressive agent were only 10, which was too small to indicate that serum CXCL9 and CXCL11 are potential biomarker to predict response to immunosuppressive therapy. -> We thank the reviewer 2 for the comments and suggestions in our study. The authors showed the association between CXCL9, CXCL10 and CXCL11 levels and clinical variables, such as %FVC, %DLCO, A-aDO2, CRP and BALF findings in all the patient in Table 4 (page 15, 16). As the levels of these markers differed among CVD-ILD, IPAF and IPF, the correlations between these markers and clinical variables may be different among the three groups. The author should explain these points or assess the correlations in each group, respectively. -> We appreciate the comments and suggestions about the correlations between the markers and clinical variables. We also expected the correlations between these chemokines and clinical variables may be different between the CVD–ILD, IPAF, and IPF groups. However, we could not adjust pulmonary function and retrieved rate of BALF between groups because of retrospective study. The normal BALF retrieved rate is 40-70%, but the proportion of patients with BALF retrieved rate of 40% or less in the CVD-ILD group was higher than in the other groups. This made it difficult to evaluate the correlations in the CVD-ILD group. We could not assess differences in the correlations caused by background autoimmunity in a subgroup analysis (S3 Table). We need a subgroup analysis in the next prospective study. We added retrieved rate of BALF in Table1 and the sentence below at lane 343-349. As the levels of CXCL9, CXCL10, and CXCL11 differed between the CVD–ILD, IPAF, and IPF groups, we expected the correlations between these chemokines and characteristics may differ between groups. However, because of retrospective study, we were unable to adjust pulmonary function and retrieved rates of BALF between the groups and could not assess differences in the correlations caused by background autoimmunity in a subgroup analysis (S3 Table). The authors showed the association between serum CXCL9, CXCL10 or CXCL11 levels and FVC change in 10 patients who treated with corticosteroid and/or immunosuppressive agents in CVD-ILD and IPAF groups in Figure 2 (page 17). This study include 16 patients with CDV-ILD and 35 patients with IPAF. In that case, how the 41 patients in CVD-ILD and IPAF groups were treated? The majority of the patients (41 patients) in CVD-ILD and IPAF groups did not receive corticosteroid and/or immunosuppressive agents? It is unclear how the authors chose the 10 patients for the correlation analyses between serum markers and response to treatment? -> We appreciate the precise comments. In this retrospective observational analysis, the number of samples were relatively low, especially in the immunosuppressive treatment group. We need to evaluate the role as the predictive biomarkers in the next prospective study. We added the sentence below at lane 381-384. Twenty-seven of the 41 patients in the CVD–ILD and IPAF groups were treated with immunosuppressive drug, but only 10 of them had pre-treatment serum samples and respiratory function test data one year after treatment due to the retrospective study nature. Attachments Attachment Submitted filename: PONE-Comments ver2.docx https://doi.org/10.1371/journal.pone.0241719.r002
15 Oct 2020 Decision Letter - Masataka Kuwana, Editor PONE-D-20-22949R1 CXCL9, CXCL10, and CXCL11; Biomarkers of pulmonary inflammation associated with autoimmunity in patients with collagen vascular diseases–associated interstitial lung disease and interstitial pneumonia with autoimmune features. PLOS ONE Dear Dr. Kuronuma, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. This manuscript has been much improved by revisions, but our reviewers suggest some improvement of the Discussion section. I ask the authors to modify the section in the re-revised version. Please submit your revised manuscript by Nov 29 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols We look forward to receiving your revised manuscript. Kind regards, Masataka Kuwana, MD, PhD Academic Editor PLOS ONE [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: All comments have been addressed Reviewer #2: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: I think the points that I pointed out last time have been improved. One last comment, do you think that in the future you will not have to measure BALF if you measure CXCL9, CXCL10, and CXCL11 only with serum? From the results of this manuscript, I understood that. Add a vision of what to do when using this marker clinically in the future. I advise you to make the conclusion easier to understood. Reviewer #2: The authors have responded to the reviewer’s questions adequately. The manuscript has been improved. Hope to validate their findings in future prospective studies. ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review?** For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0241719.r003
Revision 2
19 Oct 2020 Author Response Reviewer #1: I think the points that I pointed out last time have been improved. One last comment, do you think that in the future you will not have to measure BALF if you measure CXCL9, CXCL10, and CXCL11 only with serum? From the results of this manuscript, I understood that. Add a vision of what to do when using this marker clinically in the future. I advise you to make the conclusion easier to understood. -> We appreciate the additional comments. We tried to present the usefulness of these serum biomarkers for clinicians. We added the sentence below at lane 361-367 (discussion), 48-50(abstract conclusions) and 392-394 (conclusions). In the future, monitoring of these serum biomarkers from the time of diagnosis could be useful in determining whether immunosuppressive therapy is initiated without BAL. In particular, when ILD worsens during follow-up, these biomarkers may enable clinicians to choose anti-inflammatory drugs or anti-fibrotic drugs. Abstract conclusions Serum CXCL9, CXCL10, and CXCL11 are potential biomarkers for autoimmune inflammation and predictors of the immunosuppressive therapy responses in ILD with background autoimmunity. Conclusions Serum CXCL9, CXCL10, and CXCL11 may reflect autoimmune inflammation of ILD and work as biomarkers to predict the response to immunosuppressive therapy in the management of ILD with background autoimmunity. Reviewer #2: The authors have responded to the reviewer’s questions adequately. The manuscript has been improved. Hope to validate their findings in future prospective studies. -> We thank the reviewer 2 for the comments in our study. We plan to validate in the next prospective study. Attachments Attachment Submitted filename: PONE-Comments ver3.docx https://doi.org/10.1371/journal.pone.0241719.r004
20 Oct 2020 Decision Letter - Masataka Kuwana, Editor CXCL9, CXCL10, and CXCL11; Biomarkers of pulmonary inflammation associated with autoimmunity in patients with collagen vascular diseases–associated interstitial lung disease and interstitial pneumonia with autoimmune features. PONE-D-20-22949R2 Dear Dr. Kuronuma, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Masataka Kuwana, MD, PhD Academic Editor PLOS ONE Additional Editor Comments (optional): The authors have adequately responded to the comment made by reviewer #1. Reviewers' comments: https://doi.org/10.1371/journal.pone.0241719.r005
Formally Accepted
23 Oct 2020 Acceptance Letter - Masataka Kuwana, Editor PONE-D-20-22949R2 CXCL9, CXCL10, and CXCL11; Biomarkers of pulmonary inflammation associated with autoimmunity in patients with collagen vascular diseases–associated interstitial lung disease and interstitial pneumonia with autoimmune features. Dear Dr. Kuronuma: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Prof. Masataka Kuwana Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0241719.r006

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